Placental dysfunction, most commonly manifested as preeclampsia or intrauterine growth restriction, is an important cause of maternal and fetal morbidity and mortality in both the developing and developed world. It is thought that placental dysfunction arises from abnormal trophoblast differentiation and/or invasion, events that occur in the first trimester of pregnancy, but become clinically apparent only in the late second and third trimesters. Optimal surveillance and management of placental dysfunction, as well as the development of effective therapies, have been hampered by the lack of methods for early and accurate identification of pregnancies at risk for this disorder. This project aims to develop such a method. The goal of Aim 1 will be to identify candidate Extracellular RNA biomarkers for prediction of clinically relevant placental dysfunction from a high-risk cohort. Aim 2 will focus on validation of these biomarkers in an average-risk cohort. Aim 3 will include development of a CLIA certified assay and application of this assay in a pilot randomized control trial to assess the clinical and cost impact of screening general obstetric population for risk of placental dysfunction, and referral of screen-positive patients to a higher level of surveillance. This project is a collaboration between academia (UCSD) and industry (Sera Prognostics) and will leverage existing and in-progress resources, including the Placental Dysfunction Clinic at UCSD, the plasma and serum biobank collected from average-risk pregnancies at Sera Prognostics, and the UCSD Obstetric Registry. The research team includes investigators with diverse and complementary strengths, including expertise in maternal fetal medicine, clinical research, epidemiology, genomics, bioinformatics, molecular biology, and clinical assay development. The immediate application of a simple and accurate method to predict risk of clinically relevant placental dysfunction to obstetric care will be to enable targeting of clinical resources to high-risk cases, while sparing low risk patients unnecessary anxiety. Longer term benefits will arise from using this method to increase the safety and power of clinical trials of candidate therapies by targeting high-risk patients, thus enhancing the detection of any therapeutic effects and subjecting only the patients most likely to benefit to potential risks associated with the therapy.